Age-related macular degeneration (AMD) is the most common cause of severe visual loss in the developed world, affecting more than 10 million people in the United States alone. Approximately 1 in 3 people over the age of 75 are affected to some degree. A significant fraction of this disease is genetic. In this study, we will take advantage of the fact that experienced clinicians can reliably recognize patterns of abnormal structure and function that have discoverable causes. We will couple this clinical expertise with advanced molecular and histopathologic methods to identify new AMD genes and to better understand the disease mechanisms of AMD genes that have been previously discovered. In aim 1, we will identify novel AMD loci and locus-specific AMD phenotypes by correlating the genotypes of well-characterized AMD patients and human eye donors with their ophthalmoscopic and/or histopathologic findings. In aim 2, we will identify new AMD-causing genes and new AMD-causing mutations in known AMD genes by using a novel implementation of pyrophosphate DNA sequencing to screen 13 known AMD genes and 37 candidate AMD genes for disease-causing variations. The entire coding sequence and proximal promoter of these genes will be sequenced in 400 AMD patients and 400 aged control individuals using a novel implementation of pyrophosphate sequencing. Variations found to be significantly skewed in patients or controls will be validated by assaying them in a second cohort of 400 AMD patients and 400 controls. In aim 3, we will investigate the pathophysiologic mechanisms of AMD by characterizing retinal and RPE/choroid gene expression in human donor eyes with both high risk and low risk AMD genotypes. Specifically, for each of five different AMD loci, we will analyze the retinal and RPE/choroidal RNA of five human eye donors who are homozygous for the high-risk genotype and compare these results to those obtained from five donors who are homozygous for the low-risk genotype. These studies will provide new insight into the pathophysiologic mechanisms of AMD that will be valuable for the development of more specific diagnostic methods and more effective therapies.